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Regulation of NT-PGC-1α Subcellular Localization and Function by Protein Kinase A-dependent Modulation of Nuclear Export by CRM1*

J. Chang,P. Huypens,Yubin Zhang,Chelsea M. Black,A. Kralli,T. Gettys

Published 2010 in Journal of Biological Chemistry

ABSTRACT

Peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) plays a central role in the regulation of cellular energy metabolism and metabolic adaptation to environmental and nutritional stimuli. We recently described a novel, biologically active splice variant of PGC-1α (NT-PGC-1α, amino acids 1–270) that retains the ability to interact with and transactivate nuclear hormone receptors through its N-terminal transactivation domain. Whereas PGC-1α is an unstable nuclear protein sensitive to ubiquitin-mediated targeting to the proteasome, NT-PGC-1α is relatively stable and predominantly cytoplasmic, suggesting that its ability to interact with and activate nuclear receptors and transcription factors is dependent upon regulated access to the nucleus. We provide evidence that NT-PGC-1α interacts with the nuclear exportin, CRM1, through a specific leucine-rich domain (nuclear export sequence) that regulates its export to the cytoplasm. The nuclear export of NT-PGC-1α is inhibited by protein kinase A-dependent phosphorylation of Ser-194, Ser-241, and Thr-256 on NT-PGC-1α, which effectively increases its nuclear concentration. Using site-directed mutagenesis to prevent or mimic phosphorylation at these sites, we show that the transcriptional activity of NT-PGC-1α is regulated in part through regulation of its subcellular localization. These findings suggest that the function of NT-PGC-1α as a transcriptional co-activator is regulated by protein kinase A-dependent inhibition of CRM1-mediated export from the nucleus.

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